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Elucidation of the repair mechanism of neuronal DNA damage in Alzheimer's disease based on the functional recovery of BRCA1

Research Project

Project/Area Number 20H03587
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52020:Neurology-related
Research InstitutionTokyo Metropolitan Geriatric Hospital and Institute of Gerontology

Principal Investigator

Iwata Atsushi  地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究員 (40401038)

Project Period (FY) 2020-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2023: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2022: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Keywordsアルツハイマー病 / BRCA1 / tau / Aβ / タウ / DNA傷害
Outline of Research at the Start

これまでの研究でAlzheimer病(AD)でtauとBRCA1の共凝集によるDNA傷害の蓄積が神経細胞の機能低下の直接的な原因であることを明らかにした(Mano, et al., PNAS, 2017).一方で,DNA傷害を生じるメカニズム,生じたDNA傷害がどのようにゲノムDNAを変化させるのか,神経細胞におけるBRCA1のDNA修復機構は不明であり,それらを明らかにするために以下の様な目標を立案した.
1)AβがDNA傷害を惹起するメカニズムを解明する
2)AβによるDNA傷害がゲノム構造変化と遺伝子発現に与える影響を明らかにする
3)TauとBRCA1の共凝集を阻害する方法を得る

Outline of Final Research Achievements

The applicant revealed that the accumulation of DNA damage caused by the co-aggregation of tau and BRCA1 in Alzheimer's disease (AD) is the direct cause of neuronal functional decline (Mano, et al., PNAS, 2017). On the other hand, the mechanisms by which DNA damage occurs, how the resulting DNA damage alters genomic DNA, and the DNA repair mechanism of BRCA1 in neurons are unknown, and the following goals were formulated to clarify them.1) Elucidate the mechanisms by which Aβ induces DNA damage.2) To elucidate the effects of Aβ-induced DNA damage on genomic structural changes and gene expression.

Academic Significance and Societal Importance of the Research Achievements

ADの神経細胞機能の直接的な原因が,BRCA1の機能障害によるDNA傷害の蓄積であるとすれば,tauが蓄積した進行期ADに対して抗Aβ薬は有効ではないことをよく説明する.一方でこの結果は,DNA傷害の蓄積という神経変性の直接的な原因を,BRCA1の機能回復もしくは代償によって治療可能な可能性も示している.このことを検証するため,神経細胞のゲノムDNAにおけるDNA傷害の蓄積の本態は何か,また,このようなゲノムDNA恒常性のリスクに対するBRCA1を中心とした修復機構は何かを問うこととした.

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (17 results)

All 2023 2022 2021 2020 2019

All Journal Article (12 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (5 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] CSF P-Tau181 and Other Biomarkers in Patients With Neuronal Intranuclear Inclusion Disease2023

    • Author(s)
      Kurihara M、Komatsu H、Sengoku R、Shibukawa M、Morimoto S、Matsubara T、Arakawa A、Orita M、Ishibashi K、Mitsutake A、Shibata S、Ishiura H、Adachi K、Ohse K、Hatano K、Ihara R、Higashihara M、Nishina Y、Tokumaru A、Ishii K、Saito Y、Murayama S、Kanemaru K、Iwata A
    • Journal Title

      Neurology

      Volume: 100 Issue: 10

    • DOI

      10.1212/wnl.0000000000201647

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease2023

    • Author(s)
      Kurihara Masanori、Mano Tatsuo、Eto Fumihiro、Yao Ikuko、Sato Kenichiro、Ohtomo Gaku、Bannai Taro、Shibata Shota、Ishiura Hiroyuki、Ikemura Masako、Matsubara Tomoyasu、Morishima Maho、Saito Yuko、Murayama Shigeo、Toda Tatsushi、Setou Mitsutoshi、Iwata Atsushi
    • Journal Title

      Neurobiology of Disease

      Volume: 177 Pages: 105989-105989

    • DOI

      10.1016/j.nbd.2023.105989

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Photo‐oxygenation of histidine residue inhibits α‐synuclein aggregation2023

    • Author(s)
      Nakamura Reito、Tomizawa Ikumi、Iwai Atsushi、Ikeda Tetsuo、Hirayama Kota、Chiu Yung Wen、Suzuki Takanobu、Tarutani Airi、Mano Tatsuo、Iwata Atsushi、Toda Tatsushi、Sohma Youhei、Kanai Motomu、Hori Yukiko、Tomita Taisuke
    • Journal Title

      The FASEB Journal

      Volume: 37 Issue: 12

    • DOI

      10.1096/fj.202301533r

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Correlations between cerebrospinal fluid homovanillic acid and dopamine transporter SPECT in degenerative parkinsonian syndromes2023

    • Author(s)
      Goto Ryoji、Kurihara Masanori、Kameyama Masashi、Komatsu Hiroki、Higashino Masashi、Hatano Keiko、Ihara Ryoko、Higashihara Mana、Nishina Yasushi、Matsubara Tomoyasu、Kanemaru Kazutomi、Saito Yuko、Murayama Shigeo、Iwata Atsushi
    • Journal Title

      Journal of Neural Transmission

      Volume: 130 Issue: 4 Pages: 513-520

    • DOI

      10.1007/s00702-023-02611-y

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fully automated and highly specific plasma β-amyloid immunoassays predict β-amyloid status defined by amyloid positron emission tomography with high accuracy2022

    • Author(s)
      Yamashita Kazuto、Miura Masahiro、Watanabe Shunsuke、Ishiki Kengo、Arimatsu Yuji、Kawahira Junko、Kubo Toshiko、Sasaki Katsutaka、Arai Takayuki、Hagino Kei、Irino Yasuhiro、Nagai Kota、Verbel David、Koyama Akihiko、Dhadda Shobha、Niiro Hayato、Iwanaga Shigeki、Sato Toshiyuki、Yoshida Tomokazu、Iwata Atsushi
    • Journal Title

      Alzheimer's Research & Therapy

      Volume: 14 Issue: 1

    • DOI

      10.1186/s13195-022-01029-0

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Autopsy Validation of the Diagnostic Accuracy of <sup>123</sup>I-Metaiodobenzylguanidine Myocardial Scintigraphy for Lewy Body Disease2022

    • Author(s)
      Matsubara Tomoyasu、Kameyama Masashi、Tanaka Noriko、Sengoku Renpei、Orita Makoto、Furuta Ko、Iwata Atsushi、Arai Tomio、Maruyama Hirofumi、Saito Yuko、Murayama Shigeo
    • Journal Title

      Neurology

      Volume: 98 Issue: 16

    • DOI

      10.1212/wnl.0000000000200110

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transcriptional downregulation of FAM3C/ILEI in the Alzheimer’s brain.2022

    • Author(s)
      Watanabe N, Nakano M, Mitsuishi Y, Hara N, Mano T, Iwata A, Murayama S, Suzuki T, Ikeuchi T, Nishimura M
    • Journal Title

      Human Molecular Genetics

      Volume: 31 Issue: 1 Pages: 122-132

    • DOI

      10.1093/hmg/ddab226

    • NAID

      120007186913

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and cost-effectiveness of multiple promotion methods to recruit participants to an online screening registry to facilitate Alzheimer’s disease prevention trials: observational study of website access and registration (Preprint)2021

    • Author(s)
      Sato Kenichiro、Niimi Yoshiki、Ihara Ryoko、Suzuki Kazushi、Toda Tatsushi、Iwata Atsushi、Iwatsubo Takeshi
    • Journal Title

      Journal of Medical Internet Research

      Volume: 23(7) Issue: 7 Pages: e26284-e26284

    • DOI

      10.2196/26284

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Need of care in interpreting Google Trends-based COVID-19 infodemiological study results: potential risk of false-positivity2021

    • Author(s)
      Sato Kenichiro、Mano Tatsuo、Iwata Atsushi、Toda Tatsushi
    • Journal Title

      BMC Medical Research Methodology

      Volume: 21 Issue: 1 Pages: 147-147

    • DOI

      10.1186/s12874-021-01338-2

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cohort-Specific Optimization of Models Predicting Preclinical Alzheimer’s Disease, to Enhance Screening Performance in the Middle of Preclinical Alzheimer’s Disease Clinical Studies2021

    • Author(s)
      Sato K.、Mano T.、Ihara R.、Suzuki K.、Niimi Y.、Toda T.、Iwatsubo T.、Iwata A.
    • Journal Title

      The Journal Of Prevention of Alzheimer's Disease

      Volume: 8 Issue: 4 Pages: 1-10

    • DOI

      10.14283/jpad.2021.39

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology2020

    • Author(s)
      Tanaka Hikari, Tagawa Kazuhiko, Okazawa Hitoshi et al.
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 507-507

    • DOI

      10.1038/s41467-020-14353-6

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Colocalization of BRCA1 with Tau Aggregates in Human Tauopathies2019

    • Author(s)
      Kurihara Masanori、Mano Tatsuo、Saito Yuko、Murayama Shigeo、Toda Tatsushi、Iwata Atsushi
    • Journal Title

      Brain Sciences

      Volume: 10 Issue: 1 Pages: 7-7

    • DOI

      10.3390/brainsci10010007

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Identification of novel regulators of disease-specific α-synuclein aggregation by genome wide screening using the CRISPR/Cas9 system2023

    • Author(s)
      Ikumi Tomizawa、Yung-Wen Chiu、Tatsuo Mano、Maiko Ono、Makoto Higuchi、Tatsuo Toda、Atsushi Iwata、Yukiko Hori、Taisuke Tomita
    • Organizer
      Society for Neuroscience 2023
    • Related Report
      2023 Annual Research Report
  • [Presentation] Tau-induced Aggregation of BRCA12021

    • Author(s)
      Masanori Kurihara, Tatsuo Mano, Yuko Saito, higeo Murayama, Atsushi Iwata, Tatsushi Toda
    • Organizer
      2021 Asian Oceanian Congress of Neurology
    • Related Report
      2021 Annual Research Report
  • [Presentation] Evaluation of efficacy and cost-effectiveness of promotions for recruiting online participants to Japanese Trial-Ready Cohort (J-TRC) study2021

    • Author(s)
      Kenichiro Sato, Yoshiki Niimi, Ryoko Ihara, Kazushi Suzuki, Atsushi Iwata and Takeshi Iwatsubo
    • Organizer
      CTAD 2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] Tau-induced Aggregation of BRCA1 in Tauopathies2021

    • Author(s)
      Masanori Kurihara, Tatsuo Mano, Yuko Saito, Shigeo Murayama, Atsushi Iwata, Tatsushi Toda
    • Organizer
      2021 Asian Oceanian Congress of Neurology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] タウオパチーにおけるBRCA1とtauの共凝集の検討2020

    • Author(s)
      栗原 正典, 間野 達雄, 齊藤 祐子, 村山 繁雄, 岩田 淳, 戸田 達史
    • Organizer
      第39回日本認知症学会学術集会
    • Related Report
      2020 Annual Research Report

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Published: 2020-04-28   Modified: 2025-01-30  

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